Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients.

Parkinson disease (PD) is a chronic neurodegenerative movement disorder characterized by selective loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies. Clinical manifestations include motor impairments involving tremor, bradykinesia, postural instability and rigidity. Using dHPLC method we screened exons 31, 35, 41, 48 of the Leucine-rich repeat kinase 2 (LRRK2) gene and exons 2, 6 and 7 of Parkinson protein 2 (parkin, PARK2) genes in a cohort of 216 consecutive, unrelated Slovak patients with familial or sporadic PD, including early and late onset. By this means we aimed to detect the most common pathogenic mutations within LRRK2 (Arg1441Cys, Arg1441Gly, Arg1628Pro, Tyr1699Cys, Gly2019Ser, Ile2020Thr, Gly2385Arg) and parkin genes responsible for late and early onset forms of disease, respectively. However, none of these mutations was identified in our cohort. Heterozygous point mutation p.Arg275Trp in exon 7 of parkin gene was identified in one patient with age at onset 61 years. Furthermore, we observed the presence of one exonic (LRRK2 ex 48: 7155A>G) and eight intronic polymorphisms (in LRRK2: IVS35+23T>A, IVS47-91insGCCAT, IVS47-91insGCAT, IVS47-41A>G, IVS47-9delT, IVS47-20C>T, IVS47-90A>G, in parkin: IVS2+25T>C), three of which were novel.

Elevated immunoglobulin D levels in children with PFAPA syndrome.

BACKGROUND: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome appears to be more common than generally appreciated and should be differentiated from hereditary periodic fever syndromes, particularly from mevalonate kinase deficiency (MKD). PATIENTS AND METHODS: 14 unrelated patients (7 males, 7 females) met clinical criteria for both the PFAPA syndrome and MKD. Immunoglobulin D (IgD) levels, mevalonic aciduria and mevalonate kinase (MVK) genotype was determined in all patients. RESULTS: Children experienced their first febrile episode at the age of 24.5±5.9 months (mean±SD), the clinical diagnosis of PFAPA syndrome was established with delay at 42.7±11.7 months. The duration of febrile episodes was 3.4±0.2 days, the asymptomatic interval between them lasted 5.4±0.9 weeks. Accompanying symptoms included pharyngitis (92.8%), cervical lymphadenitis (85.7%), aphthous stomatitis (21.4%), arthralgia (14.3%) and skin erythema (35.7%). Neither mevalonic aciduria nor MVK gene mutations were found in any of the subjects, however, unexpectedly, increased plasma IgD (322.2±29.2 U/l) levels were detected in all patients. CONCLUSION: Raised IgD levels may represent a non-specific epiphenomenon, which frequently accompanies PFAPA syndrome as well as MKD. Because of the overlapping clinical and laboratory features, genetic testing of the MVK gene is indicated to differentiate these two conditions, if clinical criteria for both are fulfilled.

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Genetic analysis of candidate genes modifying the age-at-onset in Huntington's disease.

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.